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J C Strefford,
L-A Sutton,
P Baliakas,
A Agathangelidis,
J Malčíková,
K Plevova,
L Scarfó,
Z Davis,
E Stalika,
D Cortese, [......],
A W Langerak,
N Chiorazzi,
S Pospisilova,
D Oscier, F Davi,
C Belessi,
L Mansouri,
P Ghia,
K Stamatopoulos,
R Rosenquist
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ABSTRACT: Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors (BcR) and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, i.e. subsets #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subsets #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%; lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically-oriented therapy.Leukemia accepted article preview online, 5 April 2013; doi:10.1038/leu.2013.98.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2013; · 8.30 Impact Factor
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A W Langerak,
P J T A Groenen,
M Brüggemann,
K Beldjord,
C Bellan,
L Bonello,
E Boone,
G I Carter,
M Catherwood, F Davi, [......],
M Hummel,
H Liu,
L Lombardia,
E A Macintyre,
B J Milner,
S Montes-Moreno,
E Schuuring,
M Spaargaren,
E Hodges,
J J M van Dongen
[show abstract]
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ABSTRACT: PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; 26(10):2159-71. · 8.30 Impact Factor
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L Véronèse,
O Tournilhac,
M Callanan,
N Prie,
F Kwiatkowski,
P Combes,
M Chauvet, F Davi,
L Gouas,
P Verrelle,
R Guièze,
P Vago,
J O Bay,
A Tchirkov
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 8.30 Impact Factor
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E Kostareli,
M Gounari,
A Janus,
F Murray,
X Brochet,
V Giudicelli,
S Pospisilova,
D Oscier,
L Foroni,
P F di Celle, [......],
A Kouvatsi,
A Anagnostopoulos,
K Thompson,
N Darzentas,
M-P Lefranc,
C Belessi,
R Rosenquist, F Davi,
P Ghia,
K Stamatopoulos
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2011; 26(5):1127-31. · 8.30 Impact Factor
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[show abstract]
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ABSTRACT: Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2011; 25(6):979-84. · 8.30 Impact Factor
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M Le Garff-Tavernier,
J Decocq,
C de Romeuf,
C Parizot,
C A Dutertre,
E Chapiro, F Davi,
P Debré,
J F Prost,
J L Teillaud,
H Merle-Beral,
V Vieillard
[show abstract]
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ABSTRACT: Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16(+)CD56(dim) cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 25(1):101-9. · 8.30 Impact Factor
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T Brugat,
N Gault,
I Baccelli,
J Maës,
A Roborel de Climens,
F Nguyen-Khac, F Davi,
H Merle-Béral,
E Gilson,
M Goodhardt,
J Delic
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2009; 24(1):246-51. · 8.30 Impact Factor
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N Darzentas,
A Hadzidimitriou,
F Murray,
K Hatzi,
P Josefsson,
N Laoutaris,
C Moreno,
A Anagnostopoulos,
J Jurlander,
A Tsaftaris,
N Chiorazzi,
C Belessi,
P Ghia,
R Rosenquist, F Davi,
K Stamatopoulos
[show abstract]
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ABSTRACT: Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, 'stereotyped' B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of 'stereotyped' cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first ( approximately 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 24(1):125-32. · 8.30 Impact Factor
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L Véronèse,
O Tournilhac,
P Verrelle, F Davi,
G Dighiero,
E Chautard,
R Veyrat-Masson,
F Kwiatkowski,
C Goumy,
P Vago,
P Travade,
A Tchirkov
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2008; 22(6):1291-3. · 8.30 Impact Factor
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E Chapiro,
I Radford-Weiss,
C Bastard,
I Luquet,
C Lefebvre,
E Callet-Bauchu,
D Leroux,
P Talmant,
M-J Mozziconacci,
F Mugneret, [......],
S Ramond,
C Terré,
E Lippert,
F Berger,
P Felman,
H Merle-Béral,
O A Bernard, F Davi,
R Berger,
F Nguyen-Khac
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2008; 22(11):2123-7. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(1):212-4. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(1):186-9. · 8.30 Impact Factor
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M Brüggemann,
H White,
P Gaulard,
R Garcia-Sanz,
P Gameiro,
S Oeschger,
B Jasani,
M Ott,
G Delsol,
A Orfao, [......],
L Foroni,
G I Carter,
M Hummel,
C Bastard, F Davi,
M-H Delfau-Larue,
M Kneba,
J J M van Dongen,
K Beldjord,
T J Molina
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ABSTRACT: Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.
Leukemia 03/2007; 21(2):215-21. · 9.56 Impact Factor
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P A S Evans,
Ch Pott,
P J T A Groenen,
G Salles, F Davi,
F Berger,
J F Garcia,
J H J M van Krieken,
S Pals,
Ph Kluin, [......],
M Hummel,
W Jung,
M Ott,
D Canioni,
K Beldjord,
C Bastard,
M H Delfau-Larue,
J J M van Dongen,
T J Molina,
J Cabeçadas
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ABSTRACT: Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.
Leukemia 03/2007; 21(2):207-14. · 9.56 Impact Factor
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J H J M van Krieken,
A W Langerak,
E A Macintyre,
M Kneba,
E Hodges,
R Garcia Sanz,
G J Morgan,
A Parreira,
T J Molina,
J Cabeçadas, [......],
M Brüggemann,
F L Lavender,
E Schuuring,
P A S Evans,
H White,
G Salles,
P J T A Groenen,
P Gameiro,
Ch Pott,
J J M van Dongen
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ABSTRACT: The diagnosis of malignant lymphoma is a recognized difficult area in histopathology. Therefore, detection of clonality in a suspected lymphoproliferation is a valuable diagnostic criterion. We have developed primer sets for the detection of rearrangements in the B- and T-cell receptor genes as reliable tools for clonality assessment in lymphoproliferations suspected for lymphoma. In this issue of Leukemia, the participants of the BIOMED-2 Concerted Action CT98-3936 report on the validation of the newly developed clonality assays in various disease entities. Clonality was detected in 99% of all B-cell malignancies and in 94% of all T-cell malignancies, whereas the great majority of reactive lesions showed polyclonality. The combined BIOMED-2 results are summarized in a guideline, which can now be implemented in routine lymphoma diagnostics. The use of this standardized approach in patients with a suspect lymphoproliferation will result in improved diagnosis of malignant lymphoma.
Leukemia 03/2007; 21(2):201-6. · 9.56 Impact Factor
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Leukemia 02/2007; 21(1):1-3. · 9.56 Impact Factor
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C Picard,
S Hayette,
C Bilhou-Nabera,
J M Cayuela,
E Delabesse,
N Frenoy,
C Preudhomme,
M Dupont,
C Bastard,
D Bories, [......],
T Fest,
M P Gaub,
V Lhéritier,
X Thomas,
C Charrin,
C Boucheix,
H Dombret,
E Macintyre,
D Fière,
J Gabert
Leukemia 01/2007; 20(12):2178-81. · 9.56 Impact Factor
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V Asnafi,
M-T Rubio,
E Delabesse,
E Villar, F Davi,
G Damaj,
I Hirsch,
N Dhédin,
J P Vernant,
B Varet,
A Buzyn,
E Macintyre
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ABSTRACT: Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (<10(-4)). Despite being comparable for all classical parameters, the incidence of relapse was significantly higher in the high MRD group (11/14 (79%)) compared to that of the low/negative MRD group (7/24 (29%)) (P = 0.009), with d100 MRD values representing an independent risk factor of relapse and disease-free survival, but not of overall survival, in multivariate analysis. These data should facilitate risk-adapted post-transplant immunosuppression and/or tyrosine kinase inhibitor therapy based on an early evaluation of MRD.
Leukemia 05/2006; 20(5):793-9. · 9.56 Impact Factor
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[show abstract]
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ABSTRACT: Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.
Leukemia 04/2006; 20(3):498-504. · 9.56 Impact Factor
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Y Vasconcelos,
J De Vos,
L Vallat,
T Rème,
A I Lalanne,
K Wanherdrick,
A Michel,
F Nguyen-Khac,
P Oppezzo,
C Magnac,
K Maloum,
F Ajchenbaum-Cymbalista,
X Troussard,
M Leporrier,
B Klein,
G Dighiero, F Davi
Leukemia 12/2005; 19(11):2002-5. · 9.56 Impact Factor
